Monoubiquitylation promotes mitochondrial p53 translocation
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Natasha D Marchenko, Sonja Wolff, Susan Erster, Kerstin Becker and Ute M Moll*
- چاپ و سال / کشور: 2007
Description
A major function of the p53 tumor suppressor is the induction of a pleiotropic apoptotic program in response to stress through transcription-dependent and -independent mechanisms. In particular, this includes a direct apoptotic role of p53 at the mitochondria. Stress-induced p53 translocation to the mitochondria with subsequent outer membrane permeabilization is a common early component in p53-mediated apoptosis in normal and transformed cells. However, the mechanism of p53 delivery to the mitochondria remains unknown. Here, we show that the cytoplasm contains a separate and distinct p53 pool that is the major source for p53 translocation to the mitochondria upon its stress-induced stabilization. Using various manipulations that enhance or diminish p53 ubiquitylation, our data provide evidence that Mdm2- mediated monoubiquitylation of p53 greatly promotes its mitochondrial translocation and thus its direct mitochondrial apoptosis. On the other hand, p53 does not require Mdm2 as a shuttler. Upon arrival at the mitochondria, our data suggest that p53 undergoes rapid deubiquitylation by mitochondrial HAUSP via a stress-induced mitochondrial p53–HAUSP complex. This generates the apoptotically active non-ubiquitylated p53. Taken together, we propose a novel model for mitochondrial p53 targeting, whereby a distinct cytoplasmic pool of stabilized monoubiquitylated p53, generated in resting cells by basal levels of Mdm2- type ligases, is subject to a binary switch from a fate of inactivation via subsequent polyubiquitylation and degradation in unstressed cells, to a fate of activation via mitochondrial trafficking.
The EMBO Journal (2007) 26, 923–934 | & 2007 European Molecular Biology Organization | All Rights Reserved 0261-4189/07 Received: 27 June 2006; accepted: 21 December 2006; published
